Systemic lupus erythematosus (SLE) is a systemic disease characterized by arthritis, serositis, vasculitis and glomerulonephritis. Although its etiology remain unknown, evidence supports the concept that systemic lupus erythematosus is a immune complex disease and that the major pathogenic antigen-antibody system consists of DNA and antibodies to DNA. Considerable research has been done on the formation and role of DNA antibodies in this disease, but the nature, physiological behavior and role of antigen, DNA, is not well characterized. The objectives of this proposal are to clarify the mechanisms of DNA clearance, DNA breakdown, and DNA tissue localization in normal experimental animals and in experimental models of SLE. We have previously described the clearance kinetics of single-stranded DNA in normal mice and have shown that the primary mechanism for DNA removal by the liver. Experiments will be performed to identify the cell in the liver responsible for removal of single-stranded and double-stranded DNA from the circulation. Once this cell is identified, factors which may alter clearance and thereby lead to the persistence of DNA in the circulation will be examined. Experiments will be conducted in mice of different strains, ages, and sex, to determine if differences in the ability to clear DNA are present, and if these differences correlate with the tendency to develop DNA antibodies and clinical disease. Immunohistological techniques to localize DNA in renal, splenic and hepatic tissues will be developed. Characterization of the physiology of circulating DNA will lead to a better understanding of the normal mechanisms for its removal in a variety of conditions, including viral and bacterial infection and neoplasia, as in autoimmune disease. Understanding the in vivo behavior of circulating DNA and its role as the antigen in SLE will provide approaches towards altering the behavior of this antigen and thereby altering the course of this potentially lethal disease.